The incidence of atherosclerosis and type 2diabetes continues to increase world-wide, and the development of new therapeutics for metabolic disease is crucial. Notably, both diseases are associated with low grade systemic inflammation characterized by increased expression of cytokines, particularly interleukin-1b. Although chronic stimulation of the innate immune system by endogenous ligands is believed to underlie these metabolic diseases, the molecular mechanisms of activation remain unclear. The Nod-like receptor (NLR) family of innate immune sensors, such as the NLRP3 inflammasome, recognize certain danger signals leading to caspase-1 activation and processing and secretion of IL-1 family cytokines. This pathway is highly regulated and requires a two-hit model of inflammasome priming and activation, but how endogenous ligands trigger these two steps is not clear. The scavenger receptor CD36 been implicated in the pathogenesis of atherosclerosis and diabetes, and binds a variety of modified endogenous ligands that accumulate in these diseases, including oxidized LDL (oxLDL), saturated fatty acids, islet amyloid polypeptide (IAPP). Notably, several of these ligands have recently been shown to be trigger the inflammasome and we hypothesize that engagement of CD36 may be a common mechanism by which this cytosolic complex senses metabolic-associated danger signals and leads to immune dysfunction. In this grant, we propose to (a) determine the role of cooperative signaling via CD36 and Toll-like receptors (TLRs) in priming the inflammasome (step 1) in response to endogenous ligands, (b) determine how engagement of CD36 contributes directly to activation of the inflammasome (step 2) through endolysosomal dysfunction and production of reactive oxygen species, and (c) test whether inhibition of CD36 in vivo blocks inflammasome activation and IL-1b production in mouse models of atherosclerosis and insulin resistance/diabetes. These studies will provide insight into the mechanisms by which the inflammasome is triggered during atherosclerosis and diabetes, and assess the potential of CD36 as a therapeutic target in the treatment of the chronic inflammation that characterizes these metabolic diseases.